The present invention relates to pharmaceutical compositions containing complexes of factor VIII antigen and factor VIII inhibitor, and their use in suppressing the production of factor VIII inhibitor.
Blood coagulation factor VIII normally circulates at extremely low yet satisfactory concentrations in the blood plasma and plays a critical role in the blood coagulation process. Unsatisfactory levels of factor VIII cause delayed clotting of the blood and severe bleeding complications in persons suffering classical hemophilia, also known as hemophilia A. As a result, hemophiliacs fail to control hemorrhage even after minor injuries and suffer numerous associated maladies.
Hemophilia A has been treated for many years by administering dosages of commercially available factor VIII to raise the factor VIII concentration in the blood to normal levels. Usually, the treatment is quite effective and allows hemophiliacs to enjoy normal lives. Six to twenty percent of hemophiliacs have immune systems that generate inhibitor to factor VIII, however, and these individuals respond unsatisfactorily to conventional factor VIII treatment. This is especially true for about two-thirds of patients with inhibitors who are so-called "high responders." Injections of factor VIII into these individuals boost inhibitor levels to very high values.
Factor VIII inhibitor consists of alloantibodies against factor VIII. The antibodies are typically of the IgG class, and are only rarely of the IgM or IgA class. The inhibitor attacks and neutralizes the commercial supplement of factor VIII, rendering it ineffective in the blood coagulation process. Levels of inhibitor are measurable in Bethesda Units.
Bleeding complications associated with factor VIII inhibitor are not limited to hemophiliacs. Autoantibodies to factor VIII may arise in non-hemophiliac patients with rheumatoid arthritis, systemic lupus erythematosus, or drug hypersensitivity, in multiparous women, and even in apparently healthy elder individuals. Symptoms similar to those associated with hemophilia occur in these individuals.
Several treatments are known to counter the immunological response against factor VIII of hemophiliacs and others carrying factor VIII inhibitor, but these treatments have not been totally satisfactory. Treatment with very high doses of factor VIII alone has succeeded in a majority of patients but is typically prolonged and extremely expensive. Moderately high doses of factor VIII alone can be effective in a much lower proportion of patients and usually in patients with the lowest titres of inhibitors. Treatment with factor IX complex or so-called prothrombin complexes is difficult to evaluate in the absence of specific assay. The use of porcine factor VIII instead of human factor VIII is a temporary measure as it is highly immunogenic. Selected preparations of pooled gammaglobulins administered intravenously are effective in lowering the inhibitor levels, but only in some cases. Extracorporeal removal of inhibitors on protein A-Sepharose is cumbersome. A combination of extracorporeal removal of inhibitors with immunosuppressive drugs, intravenous gammaglobulins and factor VIII has recently shown success, but is considered hazardous for patients whose immune systems may be damaged for other reasons.
It is accordingly an object of the present invention to provide a pharmaceutical composition and method for effectively suppressing the production of factor VIII inhibitor.
It is a further object of the invention to provide a pharmaceutical composition and method for suppressing the production of factor VIII inhibitor that is safe, relatively inexpensive, and achieves the suppression in a relatively short period of time.
It is a further object of the invention to provide a pharmaceutical composition and method for substantially completely eliminating factor VIII inhibitor from the patient.
Other objects of the present invention will be apparent from the foregoing detailed description.